Journal of
Clinical Medicine
Review
Acute Kidney Injury: Medical Causes and Pathogenesis
Faruk Turgut 1 , Alaa S. Awad 2 and Emaad M. Abdel-Rahman 3, *
Citation: Turgut, F.; Awad, A.S.;
Abdel-Rahman, E.M. Acute Kidney
Injury: Medical Causes and
Pathogenesis. J. Clin. Med. 2023, 12,
375. https://doi.org/10.3390/
jcm12010375
Academic Editors: Anja Haase-Fielitz
and Lee Ann MacMillan-Crow
Received: 21 October 2022
Revised: 27 December 2022
Accepted: 29 December 2022
Published: 3 January 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
J. Clin. Med. 2023, 12, 375. https://doi.org/10.3390/jcm12010375
1 Faculty of Medicine, Mustafa Kemal University, Antakya 31100, Hatay, Turkey
2 Division of Nephrology, University of Florida, Jacksonville, FL 32209, USA
3 Division of Nephrology, University of Virginia, Charlottesville, VA 22908, USA
* Correspondence: ea6n@uvahealth.org
Abstract: Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden
decline in or loss of kidney function. AKI is not only associated with substantial morbidity and
mortality but also with increased risk of chronic kidney disease (CKD). AKI is classically defined
and staged based on serum creatinine concentration and urine output rates. The etiology of AKI is
conceptually classified into three general categories: prerenal, intrarenal, and postrenal. Although this
classification may be useful for establishing a differential diagnosis, AKI has mostly multifactorial,
and pathophysiologic features that can be divided into different categories. Acute tubular necrosis,
caused by either ischemia or nephrotoxicity, is common in the setting of AKI. The timely and accurate
identification of AKI and a better understanding of the pathophysiological mechanisms that cause
kidney dysfunction are essential. In this review, we consider various medical causes of AKI and
summarize the most recent updates in the pathogenesis of AKI.
Keywords: acute kidney injury; prerenal AKI; acute tubular necrosis; acute interstitial nephritis;
acute glomerulonephritis; postrenal AKI
1. Introduction
Acute kidney injury (AKI) is a frequent medical challenge associated with increased
mortality, prolonged hospital stay, and the risk of chronic kidney disease (CKD) [1,2]. The
incidence of AKI varies depending on the care setting and the criteria used to define it. AKI
occurs in 10–15% of patients admitted to the hospital and its incidence has been reported to
be more than 50% in the intensive care units [3–5].
AKI occurring outside of the hospital setting is called community-acquired (CA)-AKI,
and it has been reported a common event in the population [3]. Wonnacott et al. compared
the epidemiology, risk factors and outcomes between patients with hospital-acquired (HA)
AKI (n = 334) and CA-AKI (n = 686). They showed the incidence of CA-AKI hospital
admissions to be almost double the incidence of patients with HA-AKI (4.3% vs. 2.1%) with
similar risk factors. They further showed that, while CA-AKI patients have more severe
AKI, they have similar renal outcomes and better survival [4].
The incidence of AKI has been increasing over the years, and many factors (aging
population, the rise in predisposing comorbidities, increased use of nephrotoxic agents,
and invasive procedures) may contribute to the increased incidence of AKI [5].
AKI defined by an abrupt decrease in kidney function that includes an increase in serum
creatinine (≥0.3 mg/dL within 48 h or ≥1.5 times baseline) or urine volume < 0.5 mL/kg/h
for 6 h [6]. Kidney disease is usually a silent condition, and its current diagnosis is depen-
dent on interpreting the changes in kidney function or decreased urine output. Changes in
kidney function are usually assessed by measuring solutes that are normally excreted by
the kidney (creatinine and cystatin c) and by urine output over time. Unfortunately, both
changes in serum creatinine and urine output are neither sensitive nor specific to AKI [7].
Changes in urine output might be more sensitive but appear less specific.
https://www.mdpi.com/journal/jcm
J. Clin. Med. 2023, 12, 375 2 of 11

1.1. Subclinical AKI

In some AKI cases, kidney damage may develop, but clinical manifestations and kid-
ney dysfunction may not be present, and it is called subclinical AKI [8]. These patients are
most likely to have acute tubular necrosis yet not fulfilling the creatinine-based consensus
criteria for AKI [9]. While subclinical AKI may never develop into functional AKI and the
biomarkers immediately disappear after the insult has stopped, it may occur for a short
period, and then functional AKI develops. Subclinical AKI can occur following certain
insults, such as nephrotoxicity, NSAID and contrast dyes [10].
Clinicians must differentiate between functional changes of AKI with rising serum
creatinine/decreasing urine output and structural kidney damage that may happen prior
to the functional changes. This period of time between structural damage, as identified by
biomarkers, and the functional changes occurring when there is a drop of more than 50%
of GFR offers an opportunity for earlier intervention that can help in kidney recovery.
Biomarkers such as Cystatin C (CysC), neutrophil gelatinase-associated lipocalin
(NGAL), and kidney injury molecule-1 (KIM-1) may be helpful for detecting an injury
to the kidney well before the increase in serum creatinine during subclinical AKI [8,11].
The increase in biomarkers as NGAL and KIM-1 is associated with an increased risk
of subsequent renal replacement therapy and/or mortality. CysC is a cysteine protease
inhibitor with a small molecular weight of 13 kDa [12]. It is freely filtered in the glomerulus,
almost completely reabsorbed and catabolized by proximal tubular cells with the kidney
being the sole organ clearing it [13]. Thus, CysC is more accurate than creatinine in
determining GFR. NGAL: is a 25 kDa protein that belongs to the lipocalin superfamily [14].
Haase et al. discovered that high NGAL levels were related to poor results even in the lack
of diagnostic SCr elevations in a pooled data analysis of 10 studies of patients hospitalized to
ICU [11,15]. KIM-1 is a 38.7 kDa type I transmembrane glycoprotein that is hardly expressed
in normal animal kidney tissue but may be increased following kidney insults, and thus
can serve as a marker of early kidney injury and predict adverse clinical outcomes [15,16].

1.2. AKI
The etiology of AKI is conceptually classified into three general categories: prerenal,
intrarenal, and postrenal (Table 1). Although this classification may be useful in establishing
a differential diagnosis, AKI is mostly multifactorial, and pathophysiologic features are
shared among the different categories [7]. Other factors contribute to making AKI more
complex as, in most cases, numerous factors contribute not only to AKI initiation but also
to its progression. AKI may develop more commonly after exposure to certain insults
or in susceptible groups and many common pathophysiological factors play into the
pathogenesis of AKI (Figure 1). The main focus of this review is to summarize the various
medical causes of AKI. Furthermore, we summarize the most recent research updates in
the pathogenesis of AKI.
Prerenal disease and acute tubular necrosis are two major causes of AKI in hospital-
ized patients. Depending on the study, 25–60% of AKI cases are attributed to prerenal
causes [17,18]. Maintaining a normal glomerular filtration rate (GFR) is dependent on
adequate renal perfusion. Renal hypoperfusion can be a part of a generalized decrease in
tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of
prerenal AKI. ‘True’ intravascular volume depletion or ‘effective’ intravascular volume
depletion results in compromised renal perfusion. A variety of conditions cause prerenal
AKI; volume depletion, impaired cardiopulmonary functions, renovascular disease, and
intrarenal hemodynamic changes (Table 1). The use of medications that alter renal blood
flow and intrarenal hemodynamics are also associated with AKI. In particular, antihy-
pertensive medications (e.g., diuretics, angiotensin converting enzyme inhibitors, and
angiotensin receptor blockers) can reduce intravascular volume, renal blood flow (RBF),
and/or GFR.
J. Clin. Med. 2023, 12, 375 3 of 11

Table 1. Medical causes of acute kidney injury.

Category Abnormality Possible Causes

Hemorrhage
Poor oral intake
Gastrointestinal losses (vomiting, diarrhea)
True volume depletion
Third space losses (pancreatitis, peritonitis, burns)
Renal losses (over diuresis)
Skin or respiratory losses
Congestive heart failure
Prerenal Impaired cardiopulmonary functions Pericardial tamponade
Pulmonary thromboembolism
Systemic vasodilation
Sepsis
Decreased vascular resistance Neurogenic shock
Anaphylaxis
Hepatorenal syndrome
Medications (NSAID, RAS blockers, CNIs)
Intrarenal hemodynamic changes
Hypercalcemia
Renal ischemia
Nephrotoxins
Endogenous
Tubular damage Myoglobin, hemoglobin
Tumor lysis syndrome
Exogenous
Medications (e.g., contrast agents)
Intrinsic Acute glomerulonephritis
Vasculitis
Glomerular damage
Malign hypertension
Thrombotic microangiopathies
Infections (Bacterial or viral)
Interstitial damage
Medications (Antibiotics, NSAIDs)
Renal artery/vein thrombosis
Vascular damage Vasculitis (Polyarteritis nodosa)
Atheroembolism
Intrarenal obstruction Nephrolithiasis
Benign prostate hypertrophy
Ureterolithiasis
Postrenal Prostate, bladder, rectal or cervical cancer
Extrarenal obstruction Acute neurogenic bladder
Urethral stenosis or clotting
Retroperitoneal fibrosis
Renal papillary necrosis
NSAID: Non-steroidal anti-inflammatory drugs, RAS: Renin angiotensin aldosterone system, CNIs: Calcine-
urin inhibitors.

The normal response of the kidney to decreased renal perfusion is to maximally con-
centrate the urine and reabsorb sodium to maintain or to increase intravascular volume and
normalize renal perfusion. Autoregulatory mechanisms often compensate for some degree
of reduced renal perfusion, and initially, the glomerular and tubular function remains nor-
mal. When the hypoperfusion is sustained or the adaptive response is inadequate, organ
damage can occur. However, reduced RBF eventually leads to ischemia and cell death.
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 4 of 12

J. Clin. Med. 2023, 12, 375 4 of 11

Figure 1. Risks and Pathogenesis of AKI.

Figure 1. Risks and Pathogenesis of AKI
2. Specific Causes for Pre-Renal AKI
2.1.Prerenal
Cardio-Renal Syndrome
disease Type 1tubular necrosis are two major causes of AKI in hospital-
and acute
An acuteDepending
ized patients. worsening on of cardiac function
the study, (type 1ofcardio-renal
25%–60% AKI cases are syndrome)
attributedcantolead to a
prerenal
reduction in effective circulatory volume and an increase in central venous
causes [17,18]. Maintaining a normal glomerular filtration rate (GFR) is dependent on ad- pressure. Both
result renal
equate in inadequate
perfusion. RBF, which
Renal activates the renin
hypoperfusion can beangiotensin
a part of aaldosterone
generalized system and in
decrease
the sympathetic nervous system. On the other hand, elevated central venous pressure
tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of
results in renal venous hypertension and increased renal resistance, which causes a further
prerenal AKI. ‘True’ intravascular volume depletion or ‘effective’ intravascular volume
deterioration in renal perfusion [19].
depletion results in compromised renal perfusion. A variety of conditions cause prerenal
AKI;
2.2. volume depletion,
Hepatorenal Syndrome impaired cardiopulmonary functions, renovascular disease, and
intrarenal hemodynamic
Hepatorenal syndrome changes
(HRS)(Table
is one1).ofThe
manyusepotential
of medications
causes that alter renal
of kidney blood
dysfunc-
flow and intrarenal hemodynamics are also associated with AKI. In particular,
tion occurring in patients with hepatic cirrhosis. Based on the rapidity of the decline in antihyper-
tensive
kidneymedications
function, two(e.g., diuretics,
types of HRSangiotensin
were identified. converting
Type 1 enzyme inhibitors,
is a rapidly and angio-
progressive con-
tensin
ditionreceptor blockers)
that leads to AKI,can reduce
while renalintravascular volume,slowly
function deteriorates renal blood flow (RBF),
over weeks and/or
to months
GFR.
in type 2 hepatorenal syndrome [20]. HRS remains a diagnosis of exclusion. The kidneys
do not
Thesustain
normalany structural
response damage
of the kidney andto any identifiable
decreased renalcause of kidney
perfusion is todysfunction
maximally con- is
not apparent.
centrate the urine and reabsorb sodium to maintain or to increase intravascular volume
The pathophysiology
and normalize renal perfusion.of HRS is not fully understood,
Autoregulatory mechanisms but the complex
often compensate interaction
for some
between several different factors is implicated [21]. Arterial vasodilation
degree of reduced renal perfusion, and initially, the glomerular and tubular function re- in the splanchnic
circulation
mains normal.appears
Whentothe play a central role. is
hypoperfusion In sustained
patients with hepatic
or the cirrhosis,
adaptive vasodilators,
response is inade-
particularly nitrous oxide, increase due to increased production and decreased hepatic
quate, organ damage can occur. However, reduced RBF eventually leads to ischemia and
clearance. Splanchnic vasodilation is an important factor causing reduced effective circulat-
cell death.
ing volume, resulting in renal hypoperfusion [21,22]. Cardiomyopathy related to hepatic
cirrhosis may also contribute to the development of the HRS. Certain precipitating fac-
2. Specific Causes for Pre-Renal AKI
tors (spontaneous bacterial peritonitis, gastrointestinal bleeding, or infections) can further
2.1. Cardio-Renal
disturb Syndrome
the delicate Type 1 hemodynamic balance and can be identified in some
compensatory
patients with hepatorenal syndrome.
An acute worsening of cardiac function (type 1 cardio-renal syndrome) can lead to a
reduction in effective circulatory volume and an increase in central venous pressure. Both
result in inadequate RBF, which activates the renin angiotensin aldosterone system and
the sympathetic nervous system. On the other hand, elevated central venous pressure re-
sults in renal venous hypertension and increased renal resistance, which causes a further
deterioration in renal perfusion [19].
J. Clin. Med. 2023, 12, 375 5 of 11

3. Intrarenal Causes of AKI

Intrarenal causes of AKI can be categorized based on the primarily affected compo-
nents of the kidney, including glomeruli, interstitium, tubules, or vascular components
(Table 1).

3.1. Acute Tubular Necrosis

Acute tubular necrosis (ATN) is the most common cause of intrarenal AKI in hospi-
talized patients. Renal ischemia, sepsis, and nephrotoxins are major causes of ATN. With
prolonged ischemia, ATN can occur, which is also known as ischemic ATN. All conditions
associated with the prerenal disease can cause ATN, but ischemic ATN may also occur
in the absence of overt hypotension in conditions when renal autoregulation is impaired.
Kidney damage most commonly occurs in patients with severe hypotension, especially
in those with sepsis. Other causes of ATN include endogenous compounds (hemoglobin
in hemolysis or myoglobin in rhabdomyolysis) and exogenous compounds (drugs or ra-
diocontrast media) that directly damage renal tubules via several different mechanisms.
Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis
of ATN. ATN occurs in multiple phases. In the initial phase, prolonged hypoxia following
an ischemic event causes injury in the renal endothelial and tubular epithelial cells with
a combination of both necrosis and apoptosis. As the injury worsens, the release of pro-
inflammatory molecules induces an inflammatory cascade. Necrotic cellular debris may
cause intratubular obstruction. During the maintenance phase, cellular repair, apoptosis,
and proliferation occur to maintain cellular and tubular integrity. In the recovery phase,
blood flow returns to the normal range, and the cells re-establish intracellular homeostasis
and polarity.

3.2. Sepsis-Associated AKI

Sepsis is the most common trigger of severe AKI in critically ill patients [23,24].
Sepsis associated with ATN is often related to severe and sustained prerenal factors. The
underlying mechanisms also include the release of cytokines, kidney inflammation, and
tissue edema. Endotoxemia causes the activation of vasoactive hormones, induction of
nitric oxide synthase, the release of cytokines, and activation of neutrophils [25,26].
More specifically, sepsis can alter the immune system and immune responses, with
activation of the complement system and cellular innate immunity leading to the cell
apoptosis/death pathway. The complement system can be directly or indirectly activated
in patients with sepsis and contributes the pathogenesis. Sepsis was also found to alter
microcirculation flow with kidney tissue hypoperfusion and hypoxia. Other mechanisms
suggested to explain sepsis-induced AKI include the release of micro-RNAs causing cell
death by repressing target protein expression at the post-transcriptional level and effero-
cytosis (clearance of dead cells by phagocytes) activation by sepsis leading to an increase
in inflammatory mediators by dying cells during AKI, which attracts infiltrating immune
cells and exacerbate tissue injury [27,28].

3.3. Rhabdomyolysis
Rhabdomyolysis is characterized by the breakdown of skeletal muscle resulting in
the subsequent leakage of muscle cell contents (e.g., myoglobin, sarcoplasmic proteins,
enzymes and electrolytes) into the extracellular fluid and circulation [29]. AKI due to
rhabdomyolysis is quite common. Although the true incidence of AKI in rhabdomyolysis is
difficult to establish, the reported incidence ranges from 13% to 50% of all cases. Myoglobin,
creatine phosphokinase, and lactate dehydrogenase are the most important substances
for muscle damage. These substances may be filtered through the glomeruli, leading to
intratubular obstruction, inflammation, tubular damage, and renal vasoconstriction, and
ultimately, the development of AKI [30]. Extracted fluid from the circulation into the
swollen muscle groups leads to hypotension and shock.
J. Clin. Med. 2023, 12, 375 6 of 11

3.4. Tumor Lysis Syndrome

Tumor lysis syndrome can occur before or after chemotherapy in patients with can-
cer. It is more common in rapidly growing hematologic malignancies, particularly dur-
ing initial chemotherapeutic treatment. However, it can also be caused by solid organ
tumors, although this is quite rare. The shift of electrolytes and nucleic acid material
into the extracellular space may result in AKI. Acute uric acid nephropathy or parenchy-
mal and tubular deposition of calcium phosphate crystals are the main factors causing
AKI [31].

4. Contrast-Induced AKI
AKI may occur following the intravenous administration of contrast agents. Several
mechanisms can contribute to the contrast agent nephrotoxicity. Suggested mechanisms
include renal ischemia, vasoconstriction, formation of reactive oxygen species and direct
tubular toxicity [32]. AKI that is secondary to contrast agents may present a mixed and
picture of prerenal with the vasoconstriction ATN with the tubular toxicity.

4.1. Myeloma-Cast Nephropathy

Multiple myeloma is a cancer of plasma cells, with almost half of these patients having
some sort of kidney-related disease and up to 20% have severe AKI. Severe AKI is usually a
consequence of myeloma cast nephropathy, caused by high levels of immunoglobulin-free
light chains.
Furthermore, several other factors can contribute to AKI in patients with multiple
myeloma. The association between multiple myeloma with infection, dehydration, hyper-
calcemia and bone pain, leading to prescription of non-steroidal anti-inflammatory drugs
can all contribute to AKI in these patients [33].

4.1.1. Acute Interstitial Nephritis

Acute interstitial nephritis (AIN) can be secondary to many conditions. Medications
are the most common cause, but acute interstitial nephritis may also be caused by infection,
infiltrative disease, or simply idiopathic disease. Many drugs can cause acute interstitial
nephritis, and the most common drugs are proton pump inhibitors, NSAID, penicillin, and
cephalosporin (Table 2).

Table 2. Medications associated with AKI.

Aminoglycosides (Tobramycin, gentamycin)

Vancomycin
Antibiotics β-Lactam antibiotics
Fluoroquinolones
Rifampin
Tenofovir
Cidofovir
Antiviral agents Foscarnet
Acyclovir
Indinavir
Antifungals Amphotericin B
Analgesics NSAIDs (Naproxen, ibuprofen)
Cisplatin
Ifosfamide
Chemotherapeutic agents Tyrosine kinase inhibitors
PD-1/PD-L1 inhibitors
CTLA-4 inhibitors
J. Clin. Med. 2023, 12, 375 7 of 11

Table 2. Cont.

Lithium
Phenytoin
Proton pump inhibitors
Other agents Furosemide
Zoledronic acid
Intravenous immunoglobulin
Iodinated contrast media
NSAID: Non-steroid anti-inflammatory drugs, PD-1: Programmed cell death protein 1, PD-L1: Programmed
death ligand 1, CTLA-4: T-lymphocyte-associated protein 4.

Drug-induced AIN is produced by idiosyncratic delayed type IV hypersensitivity

reaction, but the precise pathophysiological mechanism is not fully understood.

4.1.2. Renal Parenchymal Disease

Renal parenchymal diseases other than ATN is another important cause of intrinsic
AKI. In general, the two types of renal parenchymal diseases that cause AKI are rapidly
progressive glomerulonephritis and acute proliferative glomerulonephritis. Glomeru-
lonephritis accounts for about 10% of AKI [34]. A nephritic or nephrotic pattern is observed
in renal parenchymal diseases. Acute glomerulonephritis, characterized by proteinuria,
hematuria, and hypertension (nephritic pattern) frequently causes AKI. A nephrotic pat-
tern indicates non-proliferative glomerulopathy and is a rare cause of AKI. Most cases of
glomerulonephritis are caused by an autoimmune response. The immunologic responses
trigger an inflammatory process (e.g., complement activation, leukocyte migration and
release of growth factors and cytokines) and the proliferation of glomerular tissue that
can result in damage to the basement membrane, capillary endothelium, or mesangial
area. Inappropriate complement activation contributes to the pathogenesis of AKI [35].
Complement system activation is not only a proximal trigger of downstream inflammatory
events, but may also account for the systemic inflammatory events in renal parenchymal
diseases. Acute glomerulonephritis can be caused by a primary renal disease or as part of
systemic disease (Table 3).

Table 3. Acute glomerular diseases causing AKI.

Diffuse proliferative lupus nephritis

ANCA-associated vasculitis
Goodpasture’s syndrome
Systemic disease
Thrombotic microangiopathies (HUS/TTP)
Polyarteritis nodosa
Cryoglobulinemia
Anti-glomerular basement membrane disease
Post-infectious glomerulonephritis
Renal disease
Membranoproliferative glomerulonephritis
IgA nephropathy
HUS: Hemolytic uremic syndrome, TTP: Thrombotic thrombocytopenic purpura. ANCA: Antineutrophil Cyto-
plasmic Antibodies.

4.1.3. Vascular Disease

Acute events involving small- and large-sized blood vessels can cause AKI. Neverthe-
less, the bilateral involvement or involvement of a solitary functioning kidney is necessary
for AKI development in diseases affecting larger vessels.
Acute renal artery occlusion because of thrombosis or aortic dissection results in a
renal infarct. Emboli originating from the heart, or the aorta (athero-emboli) may also lead
to renal artery obstruction. Thrombosis may spontaneously occur in a renal artery or after
trauma, surgery or angiography. Acute renal vein thrombosis is a rare clinical entity and is
generally associated with nephrotic syndrome.
J. Clin. Med. 2023, 12, 375 8 of 11

Small vessel diseases include vasculitis and diseases, presenting with thrombotic
micro-angiopathy. Small vessel vasculitis usually present as rapidly progressive glomeru-
lonephritis [36]. Thrombotic micro-angiopathies occur in a range of conditions, including
thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, HELLP (hemolysis,
elevated liver enzymes, and low platelets) syndrome, and malignant hypertension [37].
In many cases, these pathogenetic mechanisms are multifactorial in thrombotic micro-
angiopathies. Thrombi in capillaries and arterioles and endothelial injury are characteristic
findings of renal biopsy.
Renal atheroembolic disease is another common cause of vascular damage. During an-
giography or angioplasty, catheter manipulations disrupt the atheroma plaques, exposing
the soft, cholesterol-laden core of the plaque to the arterial circulation [38]. In the same way,
during surgical procedures, mechanical trauma (manipulation of the vessel or clamping)
may also disrupt the atherosclerotic plaques. Irregularly shaped cholesterol crystal emboli
can cause partial or complete obstruction of small renal arteries in atheroembolic renal dis-
ease. This causes distal ischemia and is followed by more tissue necrosis and inflammation.
Furthermore, the renin angiotensin aldosterone system and complement activation also
contribute to the development of AKI.

5. Specific Etiologies of AKI Affecting Multiple Renal Structures

5.1. Medications
AKI can be caused by various medications, but certain medications are more likely
to cause AKI (Table 2). AKI associated with medications is reported in 14.4–37.5% of
adults in different studies, depending on the definition and study population [24,39].
Medications induce various forms of kidney injury. The tubule–interstitial compartment
is the most commonly affected area in the kidney. Acute interstitial nephritis is the most
commonly reported histological manifestation of drug-induced AKI. Immune-mediated
infiltration of immune cells in the tubule–interstitium or intratubular crystal deposition
induced inflammation and renal hemodynamic deterioration are putative mechanisms in
the pathogenesis [40].
AKI may develop after the administration of iodinated contrast media. However, it is
not possible to exclude other causes of AKI in patients who developed AKI after contrast
media administration. Therefore, AKI occurring after the administration of iodinated
contrast media is currently called ‘contrast-associated AKI’ or ‘post-contrast AKI’. Studies
reported evidence of ATN. Alterations in vasoactive peptides result in renal vasoconstric-
tion and medullary hypoxia. The cytotoxic effects of the contrast agents on tubular cells
also contribute to ATN [41,42].

5.2. Infections
Infections cause several forms of renal injuries, including AKI, acute or chronic
glomerulonephritis, and tubule–interstitial nephritis. Bacterial, viral, and other infections
may induce AKI. Bacterial pyelonephritis can cause AKI only if it is severe and bilateral.
Kidney damage may occur through a direct invasion by the offending microorganisms or
immune mechanisms involving microbial organisms. Kidney injuries may also occur as a
part of sepsis-associated multi-organ failure [43].

5.3. COVID-19-Associated AKI

In patients with COVID, kidney involvement is frequent and associated with worse
outcomes [44]. Clinical presentation ranges from mild proteinuria to progressive AKI. ATN
and glomerular injury seem to be the most common cause of AKI [45,46]. It is largely
unknown whether AKI is due to hemodynamic changes and cytokine release or direct viral
cytotoxicity. The enhanced release of inflammatory mediators can play a key mechanism
in tissue damage of patients with COVID-19. Acute tubular, glomerular and endothelial
injuries are the most common histological findings. Thrombotic microangiopathy findings
were also observed in kidneys of patients who died from COVID-19. Non-specific factors,
J. Clin. Med. 2023, 12, 375 9 of 11

such as mechanical ventilation, hypoxia, hypotension, low cardiac output and nephrotoxic
agents may also contribute to kidney injury in severely affected patients [47]. Similar
to previously reported descriptions in other viral infections, collapsing glomerulopathy
has also been reported in patients with COVID-19 and has been described as COVID-19-
associated nephropathy (COVAN) [47]. The carriers of apolipoprotein L1 (APOL1) risk
variants are considered to be at particular risk of COVAN [47,48].

5.4. Post-Renal Causes of AKI

Anatomic obstruction of the urinary system at any level may result in AKI. Uri-
nary tract obstruction is commonly caused by stones, external compression by tumors,
retroperitoneal fibrosis, and bladder or prostate disorders (Table 1). Between 5 and 10%
of all AKI episodes are caused by urinary tract obstruction [17]. This incidence increases
in the elderly, but it is lower in patients with hospital-acquired AKI than in those with
community-acquired AKI [17,23,49]. Benign prostatic hyperplasia is the most common
cause of obstruction in older men. Impaired kidney function due to urinary tract obstruction
is called obstructive nephropathy.
For AKI to develop, bilateral ureter obstruction or unilateral obstruction in a single
functioning kidney or obstruction below the bladder must occur. Either complete or incom-
plete obstruction may cause AKI. A complete obstruction causes anuria, but incomplete
obstruction may be associated with varying urine volumes from low to normal or polyuria.
In patients with unilateral obstruction, serum creatinine levels usually remain normal.
Though the exact pathogenesis of AKI from urinary obstruction is not fully under-
stood, various mechanisms have been identified in experimental studies. Following acute
obstruction, the intraluminal pressure is directly reflected in the tubules and Bowman’s
space within the first few hours. Subsequently, filtration pressure and capillary perme-
ability decrease in the glomeruli. After 2–3 h of obstruction, renal plasma flow increases
due to prostaglandins to maintain GFR by overcoming the elevated intratubular pressure.
However, after 24–48 h, vasoconstriction in afferent and efferent arterioles occurs and renal
plasma flow decreases due to the increase in thromboxane A2 [50,51]. For the detection of
obstructions, the radiographic imaging of the urinary collecting system is essential [52,53].
The extent of renal recovery is influenced by the duration and severity of obstruction.

6. Conclusions
AKI often has more than one cause. Decreased renal perfusion is the most common
cause of community acquired AKI and ATN is the most common cause of AKI in hospi-
talized patients. All clinical phenotypes of AKI cannot share a single pathophysiologic
pathway. AKI is generally asymptomatic until the late stage. The past medical history, the
timing of onset of AKI, and detailed physical examination are particularly important to
identify the underlying etiology. Identifying causes is crucial because timely treatment can
reverse the decline in GFR.

Author Contributions: Concept: F.T. and E.M.A.-R.; Writing: F.T., A.S.A. and E.M.A.-R.; Revision:
E.M.A.-R. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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